Inhibition of MurA Enzyme from Escherichia coli and Staphylococcus aureus by Diterpenes from Lepechinia meyenii and Their Synthetic Analogs

Abstract

Enzymes MurA and MurF, involved in bacterial cell wall synthesis, have been validated as targets for the discovery of novel antibiotics. A panel of plant-origin antibacterial diterpenes and synthetic analogs derived therefrom were investigated for their inhibitory properties on these enzymes from Escherichia coli and Staphylococcus aureus. Six compounds were proven to be effective for inhibiting MurA from both bacteria, with IC50 values ranging from 1.1 to 25.1 µM. To further mechanistically investigate the nature of binding and to explain the activity, these compounds were docked into the active site of MurA from E. coli. The aromatic ring of the active compounds showed a T-shaped π–π interaction with the phenyl ring of Phe328, and at least one hydrogen bond was formed between the hydroxy groups and Arg120 and/or Arg91. The results disclosed here establish new chemical scaffolds for the development of novel entities targeting MurA as potential antibiotics to combat the threat of pathogenic bacteria, particularly resistant strains.

Advances in UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Covalent Inhibition

“…Diterpenes, secondary metabolites obtained from plants, and their analogs were explored as inhibitors of the MurA enzyme from E. coli and Staphylococcus aureus ( Funes Chabán et al, 2021 ) . This research showed that six compounds acted as potential inhibitors of MurA in both microorganisms with IC 50 values between 1.1 and 25.1 µM (07–12 in Table 1 ).…”

“…This research showed that six compounds acted as potential inhibitors of MurA in both microorganisms with IC 50 values between 1.1 and 25.1 µM (07–12 in Table 1 ). The results revealed that main interactions are made with amino acid residues Arg91, Arg120, and Phe328 ( Funes Chabán et al, 2021 ).…”

Synthesis and inhibitory activity against MurA and MurZ enzymes of 4H-pyrano[2,3-d]pyrimidine–1H-1,2,3-triazole hybrid compounds having piperidine and morpholine rings

“…3 PGN is one of the classic drug targets, but remains a notable target in the design of compounds with antimicrobial activity. 4,5 The inhibition against cell wall biosynthesis is a major target of antibiotics, including beta-lactam and glycopeptide antibiotics.…”

“…30 Recently, studies on the synthesis of compounds with inhibitory activity for MurA and MurZ enzymes mentioned above have been continued to be published. 4,[8][9][10]31,32 From the above brief reviews of the inhibitory activity of compounds having pyrimidine, 1,2,3-triazole rings as well as the sugar moiety, in this work we devised a design for the target hybrid molecule containing simultaneously 4H-pyrano [2,3-d]pyrimidine, 1H-1,2,3-triazole rings and saturated cyclic amines, including piperidine and morpholine, and it is hoped that they will exhibit activity against E. coli MurA as well as S. aureus enzymes MurA and MurZ.…”

“…3 PGN is one of the classic drug targets, but remains a notable target in the design of compounds with antimicrobial activity. 4,5 The inhibition against cell wall biosynthesis is a major target of antibiotics, including beta-lactam and glycopeptide antibiotics. The attractive selective targets to develop agents against Gram-positive and Gram-negative pathogenic bacteria are the enzymes participating in the biosynthesis of the bacterial cell wall, especially its essential component, i.e.…”